Hydroxyaminotetralincarboxamides

ABSTRACT

o-Hydroxy tetralin carboxamides, substituted with an amino group in the aliphatic ring, are dopamine agonists.

This application is a division of application Ser. No. 442,074, filedNov. 16, 1982, now U.S. Pat. No. 4,448,990.

BACKGROUND OF THE INVENTION

Aminotetralins which have dopamine-like pharmacological activity areknown. For example, Woodruff, Comp. Gen. Pharmacol., 2, 439 (1971)describes 2-amino-6,7-dihydroxy-1,2,3,4-tetralin (ADTN) and states thatit has a dopamine-like action.M7(2-dimethylamino-5,6-dihydroxy-1,2,3,4-tetralin) is also said to havedopamine-like activity--see Cannon et al., J. Med. Chem., 15, 348 (1972)and Long et al. J. Pharm. Exper. Therap., 192, 336 (1975). Its actionparallels that of apomorphine. The 6,7-dihydroxy isomer is also said tobe a presynaptic dopamine receptor agonist, according to Lander et al.,Science, 210, 1141 (1980).

Derivatives of 5-hydroxy-6-methyl-2-amino-1,2,3,4-tetralin are disclosedin Cannon et al., J. Med. Chem., 23, 750 (1980). Cannon et al., ibid,24, 1113 (1981) review the chemistry and pharmacological activity ofaminohydroxytetralins.

Belgian Pat. No. 861,516 and West German Pat. No. 2,803,582 disclose1-mesylamido-2-hydroxy-6-amino (ordialkylamino)-5,6,7,8-tetrahydronaphthalene and2-mesylamido-3-hydroxy-7-amino (ordialkylamino)-5,6,7,8-tetrahydronaphthalene, both said to bedopamine-like compounds.

Japanese researchers at Takeda have disclosed1-hydroxymethyl-2,5-dihydroxy-6-isopropylamino-5,6,7,8-tetrahydronaphthalene,and have stated that it is a bronchodilator--see Arzneim. Forsch./Drug.Res., 30, 276 (1980).

In related pharmacological areas, U.S. Pat. No. 4,101,677 claims1-alkylamino (or dialkylamino)-1,2,3,4-tetralins, useful in inducinganesthesia; and U.S. Pat. No. 4,320,148 describes 5 and8-substituted-2-amino-1,2,3,4-tetralins with central α-agonist actionwhere the substituents are methoxy, methylthio, ethylthio, phenylthioand trifluoromethylthio.

The above references are not cited as a complete review of thevoluminous aminohydroxytetralin literature, but do include publicationsdescribing dopamine-like compounds with those structural characteristicsplus a few other recent patents in the general field.

A search of the chemical literature has uncovered nocarboxamido-substituted hydroxyaminotetralins, such as are disclosed andclaimed herein.

DESCRIPTION OF THE INVENTION

This invention provides carboxamido-substituted hydroxyaminotetralins(or tetrahydronaphthalenes) of the formula ##STR1## wherein one of R andR¹ is H and the other is a carboxamido group, and R² and R³ areindividually H, methyl, ethyl or n-propyl; and pharmaceuticallyacceptable acid addition salts thereof. These compounds are dopamineagonists and are therefore useful in inhibiting prolactin secretion,alleviating the symptoms of Parkinsonism and reducing blood pressurelevels in mammals having elevated blood pressure.

When R is carboxamide and R¹ is H, the compounds have the followingformula ##STR2## and are named as dl(or±)-2-hydroxy-6-amino-5,6,7,8-tetrahydronaphthalene-1-carboxamides. Whenthe reverse is true; i.e., R is H and R¹ is carboxamide, the ringnumbering is also changed and the compounds (Ib) ##STR3## are named asdl(or ±)-3-hydroxy-7-amino-5,6,7,8-tetrahydronaphthalene-2-carboxamides.The "dl" refers to the fact that the carbon carrying the amine functionis asymmetric, thereby giving rise to two optical isomers occurring as aracemic mixture. This invention includes within its scope dopamineagonists of formula I, whether as a racemate or as the d or l componentsthereof.

Also included within the scope of this invention are intermediatesuseful in preparing the above compounds, said intermediates having thestructure ##STR4## wherein one of R⁴ and R⁵ is H and the other is##STR5## R⁶ is H or benzyl and R⁷ and R⁸ are individually H, methyl,ethyl or n-propyl.

Pharmaceutically-acceptable acid addition salts of the compounds of thisinvention include salts derived from non-toxic inorganic acids such as:hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,hydrobromic acid, hydriodic acid, phosphorous acid and the like, as wellas salts derived from non-toxic organic acids such as aliphatic mono anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicand alkandioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such pharmaceutically-acceptable salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylte, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

The compounds of this invention are prepared, by chemically similarroutes, the route depending on whether a compound according to Ia or Ibis desired. These routes are set forth in Reaction Schemes A-G below. Inthe various formulas in the separate reaction schemes, compounds havinga single mono-valent substituent [OH, N₃, NH₂, N(alk)₂, etc.] in thetetrahydro portion of the tetrahydronaphthalene; e.g. I, Ia, Ib, VII,VIII, X, XII, XIII, XIV, XV, XXI, XXII, XXIII, XXV, XXVII, XXVIII, XXIX,XXX, XXXVI, XXXIX, XXXX, XXXXI and XXXXII have an asymmetric center atC-6 (in the 1-naphthoates) or at C-7 (in the 2-naphthoates), the pointof attachment of the monovalent group. Such compounds exist and areprovided herein as a pair of stereoisomers occurring as a racemate.

In certain structures, asymmetric carbons are present at both C-5 andC-6 (in the 1-naphthoic acid series) or at C-7 and C-8 (in the2-naphthoic acid series); e.g., IX, XIX, XX, XXIV, XXXII, XXXVII andXXXVIII. Compounds with two asymmetric centers exist as fourstereoisomers, occurring as two racemic pairs. Formulas bearing theabove numbers, while two dimensional, are intended to represent the3-dimensional individual enantiomers as well as the optically neutralracemates, made up of molecular compounds each containing a pair ofstereoisomers.

A convenient preparation of compounds in which the carboxamide group isto be at C-7 (formula I above wherein R is H and R¹ is carboxamide, alsoformula Ib), begins with commercially available 3-hydroxy-2-naphthoicacid. The process of converting this compound to Ib is illustrated inthe first part of Reaction Scheme A. As set forth therein, the hydroxyacid is first converted to the corresponding methyl ester (III)according to the procedure of J.A.C.S., 76, 5761 (1954) utilizingdimethyl sulfate in the presence of potassium bicarbonate as themethylating system. Other esterification systems can be used as will beapparent to those skilled in the art, and other lower alkyl esters canbe prepared and are equally useful. Hydrogenation of the methyl esterover a palladium-on-carbon catalyst on other suitable noble metalcatalyst, such as a platinum or rhodium catalyst, yields a tetralin,methyl 5,6,7,8-tetrahydro-3-hydroxy-2-naphthoate (IV). This 3-hydroxytetralin-2-ester is then converted to the 3-benzyl ether withbenzylchloride in the presence of potassium carbonate, a classicalWilliamson synthesis. Chromic acid oxidation of the thus-formed methyl5,6,7,8-tetrahydro-3-benzyloxy-2-naphthoate (V) yields methyl5,6,7,8-tetrahydro-3-benzyloxy-8-oxo-2-naphthoate (VI).

Reaction Scheme B gives the remainder of this first synthetic route. Thereaction of the carbonyl compound (VI) with hydroxylamine hydrochlorideproduces the corresponding oxime (XVI). The oxime is next acylated withan aryl sulfonylchloride such as benzenesulfonylchloride orp-tosylchloride to yield the aryl sulfonyloxy derivative (XVII). Thisderivative, upon treatment with a base such as potassium ethylate,rearranges to yield methyldl-5,6,7,8-tetrahydro-3-benzyloxy-8-oxo-7-amino-2-naphthoate (XXVIII),isolated in the form of its hydrochloride salt. Sodium borohydridereduction of the aminoketone yields the corresponding 8-hydroxyderivative (XIX). At this point, the amino group can be alkylated. Forexample, to prepare an N,N-di-n-propyl derivative, the amine is reactedwith at least 2 moles of propionaldehyde in the presence of sodiumcyanoborohydride. To prepare an N,N-dimethyl or N,N-diethyl derivative,formaldehyde and acetaldehyde are used in place of propionaldehyde. Theresulting product, methyldl-5,6,7,8-tetrahydro-3-benzyloxy-8-hydroxy-7-dialkylamino-2-naphthoate(XX) where R² and R³ are methyl, ethyl or n-propyl, is hydrogenatedagain using palladium-on-carbon or other suitable noble metal catalyst.This hydrogenation serves to cleave the benzyloxy function to a hydroxylgroup and to remove the 8-hydroxy function entirely. The product of thisreaction, a methyldl-N,N-dialkyl-3-hydroxy-7-amino-5,6,7,8-tetrahydro-2-naphthoate (XXI),is then converted to the corresponding amide (Ib) using ammonia inmethanol under pressure.

If it is desired to prepare compounds according to Ib where R² and R³are H, XIX is reduced and debenzylated as set forth in Reaction Scheme Afor conversion of XII to XIII (the hydroxy group is removed in thisprocedure--see Reaction Scheme B, XX→XXI. The methyldl-3-hydroxy-7-amino-5,6,7,8-tetrahydro-2-naphthoate thus prepared isreadily converted to the naphthalene-2-carboxamide by the procedure ofReaction Scheme B, XXI→Ib, where R² and R³ =H.

Alternatively, as set forth in Reaction Scheme A, methyl5,6,7,8-tetrahydro-3-benzyloxy-8-oxo-2-naphthoate (VI) can be brominatedalpha to the carbonyl group using pyridinium perbromide hydrobromide orother suitable brominating agent including molecular bromine to yieldthe corresponding 8-oxo-7-bromo derivative (VII). Reaction of this bromoderivative with sodium azide yields methyldl-5,6,7,8-tetrahydro-3-benzyloxy-8-oxo-7-azido-2-naphthoate (VIII).Reduction with sodium borohydride serves to reduce the oxo group to ahydroxy group (IX) and the hydroxy is removed by treatment withtriethylsilane in trifluoroacetic acid (TFA). The resulting 7-azidoderivative (X) is then converted to the corresponding 7-amino derivative(XII) by treatment with hydrazine and Raney nickel. At this point,hydrogenation with a palladium catalyst serves to remove the benzylprotecting group and the resulting methyldl-5,6,7,8-tetrahydro-3-hydroxy-7-amino-2-naphthoate can be converteddirectly by ammonia in methanol under pressure to yield a compound ofthis invention,dl-3-hydroxy-7-amino-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Ibwhere R² and R³ =H). Alternatively, the 7-amino derivative (XII) can bealkylated as with formaldehyde, acetaldehyde or propionaldehyde andsodium cyanoborohydride to yield the 7-N,N-dialkyl derivative (XIV),which derivative after debenzylation with hydrogen over a palladiumcatalyst followed by conversion of the ester to the amide yields anN,N-dialkyl-3-hydroxy-7-amino-5,6,7,8-tetrahydronaphthalene-2-carboxamide(Ib where R² and R³ are individually methyl, ethyl or n-propyl. ##STR6##

Compounds according to formula I wherein R¹ is H and R is carboxamido(Ia) are prepared conveniently according to the procedure of ReactionScheme C whereby methyldl-2-benzyloxy-5-oxo-6-bromo-5,6,7,8-tetrahydro-1-naphthoate (XXII)--seeChem. Pharm. Bull., 25, 2999 (1977)--is treated with sodium azide toyield the corresponding 6-azido derivative (XXIII). Reduction of thisazide with sodium borohydride yields methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (XXIV).The hydroxyl group is readily removed by treatment with triethylsilaneand trifluoroacetic acid to yield methyldl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (XXV). The6-azido group is then converted to an amino group by treatment withhydrazine and Raney nickel to provide the corresponding 6-aminoderivative (XXVII). The amino derivative can then be alkylated bytreatment with a lower alkyl aldehyde (formaldehyde, acetaldehyde, orpropionaldehyde) and sodium cyanoborohydride. The resulting compound, amethyl dl-2-benzyloxy-6-dialkylamino-5,6,7,8-tetrahydro-1-naphthoate(XXVIII), upon hydrogenation with palladium-on-carbon, is debenzylatedto yield the corresponding 2-hydroxy compound (XXIX). The ester group isthen converted with hydrazine to the carboxhydrazide derivative (XXX)which can be split by treatment with Raney nickel to yield adl-2-hydroxy-6-dialkylamino-5,6,7,8-tetrahydronaphthalene-1-carboxamide(Ia). Alternatively, the 2-hydroxycarboxylic acid ester (XXIX) can beconverted directly to the carboxamide (Ia) with methanolic ammonia underpressure.

If it is desired to prepare a compound in which R² and R³ are both H,the methyl dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthoate(XXVII) can be directly debenzylated with palladium-on-carbon andhydrogen and the resulting 2-hydroxy derivative converted to the1-carboxamide either directly with methanolic ammonia or indirectly viathe hydrazide (XXIX→XXX→Ia, where R² and R³ =H). ##STR7##

The procedure utilized in Chem. Pharm. Bull. (loc. cit.) to yield thebromoketone starting material (XXII) is as follows:2-hydroxy-1-naphthoic acid, commercially available, is esterified with alower alkanol. The 2-hydroxy-1-carboxylic acid ester is thenhydrogenated over palladium-on-carbon to yield a2-hydroxytetrahydronaphthoic acid ester. The hydroxy group of thiscompound is next protected with benzyl group or other suitableprotecting group. Chromic acid oxidation yields the corresponding 5-oxoderivative which is then brominated with pyridinium perbromidehydrobromide to yield the aforementioned bromoketone starting material.

Alternatively, the methyl 2-benzyloxy-5-oxo derivative, a precursor tothe 6-bromo derivative used as a starting material in the abovesequence, can be reduced to the 5-hydroxy compound which can in turn bedehydrated to give a methyl 2-benzyloxy-7,8-dihydro-1-naphthoate (XXXI).The same compound can be prepared from the 5-oxo-6-bromo derivative(XXII) by reduction of the carbonyl group to hydroxyl and removal of theelements of HOBr to yield the 5,6-unsaturated derivative (XXXI).According to Reaction Scheme D, peroxidation of this compound withm-chloroperbenzoic acid or other suitable agent in the presence ofethanol yields a 5-ethoxy-6-hydroxy derivative (XXXII) which compound,on treatment with acid, produces methyldl-2-benzyloxy-6-oxo-5,6,7,8-tetrahydro-1-naphthoate (XXXXII). The6-oxoderivative is then converted to the 6-amino derivative (XXVII) withammonium acetate and sodium cyanoborohydride. Conversion of XXVII to Iawhere R² and R³ =alkyl is set forth in Reaction Scheme C. ##STR8##

In a still different procedure (Reaction Scheme E below), in which theorder of steps is somewhat changed, the methyldl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (XXV) can betreated with ammonia in methanol under pressure to yield thecorrespondingdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydronaphthalene-1-carboxamide(XXXIX). Conversion of the azide group to an amino group with hydrazineand Raney nickel yields adl-2-benzyloxy-6-amino-5,6,7,8-tetrahydronaphthalene-1-carboxamide(XXXXI). This compound can be treated directly with hydrogen in thepresence of a palladium catalyst to remove the benzyl group and yield acompound according to formula Ib above wherein R² and R³ are bothhydrogen. Alternatively, the benzyloxy derivative can be alkylated witha lower aldehyde and sodium cyanoborohydride to yield adl-2-benzyloxy-6-dialkylamino-5,6,7,8-tetrahydronaphthalene-1-carboxamide(XXXXI) which compound, upon treatment with hydrogen in the presence ofa palladium catalyst, yields a compound of this invention (Ib) where R²and R³ are individually Me, Et or n-Pr.

It is apparent that Reaction Schemes A and B can be similarly modifiedby preparing the carboxamide function early in the procedure rather thanas a last step, and other necessary reactions carried out on thecarboxamide. ##STR9##

Alternatively, following one of the procedures utilized to preparecompounds according to Ib above as set forth in Reaction Scheme F below,the 2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-naphthoate ester (XXXIII)(Scheme F) can be converted to the corresponding oxime (XXXIV) withhydroxylamine hydrochloride and the oxime acylated with an arylsulfonylchloride (XXXV). Rearrangement of the acyloxime with base yieldsthe 5-oxo-6-amino derivative (XXXVI). This compound is then reduced tothe corresponding 5-hydroxy compound (XXXVII). The amine group can thenbe optionally alkylated with an aldehyde and sodium cyanoborohydride(XXXVIII). Finally, the benzyl group and the 5-hydroxy group are bothremoved with hydrogen in the presence of a palladium catalyst to yield,after ammonolysis of the ester function, a compound of this invention(Ia) where R² and R³ are alkyl. ##STR10##

Finally, Reaction Scheme G illustrates an alternative procedure forproceding from an azido naphthoate ester with a protectedortho-benzyloxy group (here, the 1-naphthoate derivative XXV) to thedl-2-hydroxy-6-amino-1-naphthalenecarboxamide, via the free acid, acidchloride and amide followed by reduction of the azide group to NH₂ andlastly by debenzylation to the free 2-OH derivative. ##STR11##

In the above Reaction Sequences A-G, alkylation of the 6(7)-amino grouphas been illustrated only to produce symmetrical dialkyl derivatives (R²=R³ =Me, Et, n-Pr). If it is desired to produce monoalkyl derivatives orunsymmetrical dialkyl derivatives (R² ≠R³), such derivatives beingincluded within the scope of formulas I, Ia and Ib, the followinggeneral procedure is employed. First, the 6(7)-amino group is monoalkylated by using equimolar quantities of aldehyde and amine plus anexcess of sodium cyanoborohydride. The secondary amine thus produced,after debenzylation and amidation, has a structure according to Iwherein one of R and R¹ is H and the other is carboxamide, and one of R²and R³ is H and the other is Me, Et or n-Pr. Thealdehyde-cyanoborohydride procedure can thus be repeated, if desired, onthe secondary amino compound with a different aldehyde so as to producea compound according to I wherein R² and R³ are not the same but areindividually Me, Et or n-Pr.

This invention is further exemplified by the following specificexamples.

EXAMPLE 1 Preparation ofdl-2-hydroxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide

A solution was prepared by dissolving 8.9 g. of methyl2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-napthoate prepared by theprocedure of Chem. Pharm. Bull., 25, 2999 (1977) in 150 ml. of methanoland 150 ml. of tetrahydrofuran (THF). Nine and six tenths grams ofpyridinium perbromide hydrobromide were added and the reaction mixturestirred for about three hours, after which time it was diluted withwater and the resulting aqueous mixture extracted with chloroform. Thechloroform layer was separated and the separated layer washed withsaturated sodium chloride and then dried. Evaporation yielded methyldl-2-benzyloxy-5-oxo-6-bromo-5,6,7,8-tetrahydro-1-naphthoate as aresidue. The residue was dissolved in 200 ml. of dimethyl formamide(DMF) containing 5 ml. of glacial acetic acid. This solution was cooledto about 0° C. A solution containing 4 g. of sodium azide in 40 ml. ofwater was then added. The resulting reaction mixture was stirred andcooled for about four hours and then left at about 0°-5° C. overnight.It was then diluted with water and the aqueous mixture extracted withethyl acetate. The ethyl acetate layer was separated and the separatedlayer washed with saturated aqueous sodium chloride and then dried.Evaporation of the residue yielded methyldl-2-benzyloxy-5-oxo-6-azido-5,6,7,8-tetrahydro-1-naphthoate formed inthe above reaction.

The compound melted at 65°-7° C. with decomposition aftercrystallization from methanol.

Analysis Calculated: C, 64.95; H, 4.88; N, 11.96. Found: C, 64.64; H,4.98; N, 12.02.

The 6-azido compound was dissolved in about 200 ml. of methanol and themethanol solution cooled to about 0° C. Nine grams of sodium borohydridewere added thereto in small portions with stirring. The reaction mixturewas next stirred for about four hours and then diluted with water. Theaqueous mixture was extracted several times with equal volumes ofchloroform. The chloroform extracts were combined and the combinedextracts washed with saturated sodium chloride and then dried.Evaporation of the chloroform yielded methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydronaphthoate formed inthe above reaction. TLC over silica (ether) indicated that the solidresidue was substantially the desired product containing a small amountof starting material. Eleven grams of a viscous oil which crystallizedafter standing overnight were obtained. Methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate thusprepared melted at 65°-66° C. after recrystallization from ether.

Analysis Calculated: C, 64.58; H, 5.42; N, 11.89. Found: C, 64.60; H,5.33; N, 11.85.

Five Hundred milligrams of methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate weresuspended in 10 ml. of triethylsilane and 10 ml. of carbontetrachloride. About 5 ml. of trifluoroacetic acid were added. TLC aftera ten minute reaction time indicated that there was no longer anystarting material present and that there was only one major component inthe reaction mixture. After 25 minutes reaction time, the reactionmixture was poured over ice and the aqueous solution made basic with 14Naqueous ammonium hydroxide. The alkaline layer was extracted withchloroform. The chloroform extract was separated, washed with saturatedsodium chloride and dried and the solvent removed by evaporation. Theresidue was chromatographed over 30 g. of florisil using hexanecontaining increasing amounts (0-20%) of ether as the eluant. Fractionsshown by TLC to contain the desired product, methyldl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate, were combined.Evaporation of the solvent from the combined fractions yielded purifiedmethyl dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate whichmelted at 83°-4° C. after recrystallizaton from hexane; yield=365 mg.

Analysis Calculated: C, 67.64; H, 5.68; N, 12.46. Found: C, 67.93; H,5.71; N, 12.56.

The above reaction in which the 5-hydroxy group was eliminated by usinga triethylsilane-trifluoroacetic acid reagent was repeated on a 4.4 g.sample of methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydronaphthoate. The6-azido compound from this reaction was used without furtherpurification as follows: the residue from evaporation of the extractingsolvent was dissolved in 100 ml. of THF and 100 ml. of ethanol. About 3g. of Raney nickel were added. Next, a solution of 2 ml. of hydrazinehydrate in 10 ml. of ethanol was added in dropwise fashion to thestirred reaction mixture. The reaction mixture was filtered and thevolatile constituents removed by evaporation. This residue was dissolvedin 200 ml. of methanol. One gram of sodium cyanoborohydride was addedfollowed by 10 ml. of 37% aqueous formaldehyde. The reaction mixture wasstirred at room temperature under a nitrogen atmosphere overnight andwas then diluted with saturated aqueous sodium bicarbonate. The alkalineaqueous mixture was extracted with chloroform. The chloroform extractwas separated and the separated extract washed with saturated aqueoussodium chloride and then dried. Evaporation of the solvent yielded aresidue which, by TLC, indicated one major product contaminated with asmall amount of starting material. A chloroform solution of the residuewas chromatographed over 100 g. of florisil using chloroform containingincreasing amounts (0-4%) of methanol as the eluant. Fractions shown byTLC to contain the desired product, methyldl-2-benzyloxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthoate, werecombined in ethanol solution and the solution saturated with gaseoushydrogen chloride. The crystalline hydrochloride salt was separated byfiltration and recrystallized from an ethanol/ether solvent mixture. Oneand seven tenths grams of hydrochloride salt melting at 190°-2° C. wereobtained.

Analysis Calculated: C, 67.10; H, 6.97; N, 3.73; Cl, 9.43. Found: C,66.85; H, 7.12; N, 3.74; Cl, 9.36.

Two and thirty-eight hundredths grams of methyldl-2-benzyloxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthoatehydrochloride were dissolved in 50 ml. of methanol and hydrogenated with1 g. of palladium-on-carbon in 10 ml. of THF at a hydrogen pressure=60psi. After the theoretical quantity of hydrogen had been absorbed, thereaction mixture was taken from the hydrogenator and filtered.Evaporation of the solvent in vacuo yielded, as a residue, methyldl-2-hydroxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthoatehydrochloride formed in the above reaction. One and five tenths grams ofa solid were obtained which decomposed at about 225° C.

Analysis Calculated: C, 58.84; H, 7.05; N, 4.90; Cl, 12.41. Found: C,59.08; H, 7.34; N, 5.00; Cl, 12.26.

The solid hydrochloride salt obtained above was dissolved in water anddilute aqueous sodium bicarbonate added until the aqueous layer becamebasic. The aqueous layer was extracted several times with an equalvolume of a chloroform/isopropanol solvent mixture. The organic extractswere combined and the combined extracts washed with saturated aqueoussodium chloride and then dried. Evaporation of the solvent in vacuoyielded 1.20 g. of an oil comprising methyldl-2-hydroxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthoate free base.The oil was dissolved in a 60 ml. of methanol to which was added 10 ml.of anhydrous hydrazine. The reaction mixture was heated to refluxingtemperature for about one day and then cooled. The volatile constituentswere removed in vacuo and the residue, comprisingdl-2-hydroxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxhydrazideformed in the above reaction, was dissolved in 125 ml. of ethanol towhich were added about 2 g. of Raney nickel. This reaction mixture washeated to refluxing temperature for about one day after which time itwas cooled and filtered. Gaseous HCl was passed into the solution. Thevolatile constituents were evaporated in vacuo and the residuerecrystallized from ethanol. Four hundred and seventy mg. ofdl-2-hydroxy-6-dimethylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride were obtained melting at 249°-251°C. with decomposition.

Analysis Calculated: C, 57.67; H, 7.07; N, 10.35; Cl, 13.09. Found: C,58.00; H, 7.27; N, 10.62; Cl, 12.92.

EXAMPLE 2 Preparation ofdl-2-Hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide

Following the procedure of Example 1, 4.0 g. of methyldl-2-benzyloxy-5-hydroxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate weretreated with a mixture of triethylsilane and trifluoroacetic acid incarbon tetrachloride solution to yield methyldl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate. Still followingthe procedure of Example 1, this compound was reacted with hydrazinehydrate and Raney nickel in THF and ethanol to yield methyldl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthoate. The 6-aminocompound was dissolved in 200 ml. of methanol to which was added 1 g. ofsodium cyanoborohydride followed by 10 ml. of propionaldehyde. Thereaction mixture was stirred at room temperature under a nitrogenblanket overnight, and was then diluted with saturated aqueous sodiumbicarbonate solution. The alkaline layer was extracted with chloroform.The chloroform extract was separated and the separated extract washedwith saturated aqueous sodium chloride and then dried. Evaporation ofthe solvent in vacuo yielded a residue which was dissolved in chloroformand the chloroform solution chromatographed over 100 g. of florisilusing chloroform containing increasing quantities (0-2%) of methanol asthe eluant. Fractions containing methyldl-2-benzyloxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthoate werecombined and the solvent evaporated from the combined fractions. Theresulting residue was converted to the hydrochloride salt which meltedat 170°-1° C. after recrystallization from an ethanol/ether solventmixture; yield=3.41 g.

Analysis Calculated: C, 69.51; H, 7.93; N, 3.24; Cl, 8.21. Found: C,69.27; H, 7.66; N, 3.42; Cl, 7.94.

The product was debenzylated by hydrogenation in the presence of apalladium catalyst and the debenzylated compound converted to the amideby the procedure of Example 1.

EXAMPLE 3 Preparation ofdl-3-Hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamide

A reaction mixture was prepared from 200 g. of 3-hydroxy-2-naphthoicacid, 160 g. of potassium bicarbonate, 154 g. of dimethyl sulfate and1500 ml. of acetone. The reaction mixture was heated to refluxingtemperature for about 3 hours after which time it was diluted with waterand the resulting alkaline aqueous layer extracted with ethyl acetate.The ethyl acetate layer was separated and the separated layer washedwith water and saturated aqueous sodium chloride and then dried.Evaporation of the solvent yielded a residue which solidified upontrituration with methanol to yield 205 g. of methyl3-hydroxy-2-naphthoate melting at 72°-4° C.

Two hundred and twenty-two grams of the above ester were hydrogenated at1500 psi using 80 g. of a 5% palladium-on-carbon catalyst and 1.45 l. ofmethanol as a solvent. The hydrogenation was carried out at 70° C. andtook six hours. The hydrogenation mixture was cooled and the catalystremoved by filtration. The solvent was removed from the filtrate byevaporation to yield two crystalline fractions (total yield=144.5 g.) ofmethyl 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoate melting at 41°-2° C.

Analysis Calculated: C, 69.81; H, 6.84. Found: C, 70.13; H, 6.93.

A reaction mixture was prepared from the above quantity of ester, 50 g.of potassium carbonate, 46 g. of benzylchloride and 400 ml. ofdimethylactamide (DMA). After the reaction had gone to completion, thereaction mixture was filtered through florisil and the precipitate ofmethyl 3-benzyloxy-5,6,7,8-tetrahydro-2-naphthoate which formed wascrystallized from ethanol to yield 142.7 g. of compound melting at60°-3° C.

Analysis Calculated: C, 77.00; H, 6.80. Found: C, 77.26; H, 6.99.

A solution of 142 g. of the above ether-ester in 600 ml. of glacialacetic acid was chilled. A second solution of 100 g. of CrO₃ in 280 ml.of glacial acetic acid and 40 ml. of H₂ O was added to the first indropwise fashion. The reaction was stirred and cooled (0°-5° C.) forabout 3 hrs., after which time excess CrO₃ was destroyed by the additionof isopropanol. The reaction mixture was diluted with H₂ O and theaqueous mixture extracted with ethyl acetate. The ethyl acetate extractwas separated and washed successively with water, saturated aqueoussodium bicarbonate, water, and saturated aqueous sodium chloride. Theethyl acetate solution was dried. Concentration of the solution yieldedsolid methyl 3-benzyloxy-8-oxo 5,6,7,8-tetrahydro-2-naphthoate meltingat 111°-4° C.; yield=58 g. An additional 35 g. were obtained from thefiltrate, utilizing chromatography to remove impurities.

Forty-Three grams of methyl3-benzyloxy-8-oxo-5,6,7,8-tetrahydro-2-naphthoate were suspended in 1 l.of methanol to which was added 14 g. of hydroxylamine hydrochloride.Sixteen grams of sodium acetate were then added. The reaction mixturewas stirred at ambient temperature under a nitrogen blanket for aboutone day after which time it was diluted with water and the aqueous layerextracted with ethyl acetate. The ethyl acetate layer was separated, theseparated layer washed with water and saturated aqueous sodium chlorideand then dried. Evaporation of the solvent yielded 49 g. of methyl3-benzyloxy-8-oximino-5,6,7,8-tetrahydro-2-naphthoate melting at148°-150° C. after recrystallization from ether.

Analysis Calculated: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.33; H,5.88; N, 4.49.

Forty-Nine grams of methyl3-benzyloxy-8-oximino-5,6,7,8-tetrahydro-2-naphthoate were dissolved in300 ml. of pyridine and the solution cooled to about 0° C. Twenty-threeml. of benzenesulfonylchloride were added slowly. After the addition hadbeen completed, the reaction mixture was stirred at about 0° C. forabout 1.75 hours. The reaction mixture was kept at 0°-5° C. overnightand was then diluted with water and the resulting aqueous mixtureextracted with chloroform. The organic layer was separated and theseparated layer washed with saturated aqueous sodium chloride and thendried. Evaporation of the solvent in vacuo yielded a residue which wasdissolved in chloroform and the chloroform solution filtered through 300g. of florisil. TLC showed one major spot. The residue from the florisilfiltration procedure was recrystallized from ether to yield 51 g. ofmethyl3-benzyloxy-8-O-benzenesulfoximino-5,6,7,8-tetrahydro-2-naphthoateformed in the above reaction melting at 125°-8° C. Recrystallizationfrom methanol yielded crystals melting 171°-2° C. An additional 2 g. ofmaterial were obtained from the mother liquors.

Analysis Calculated: C, 64.50; H, 4.98; N, 3.01; S, 6.89. Found: C,64.74; H, 5.06; N, 2.95; S, 6.78.

The benzenesulfoximino compound was rear-ranged with alkali according tothe following procedure: One and five tenths grams of methyl3-benzyloxy-8-benzenesulfonyloximino-5,6,7,8-tetrahydro-2-naphthoatewere dissolved in 40 ml. of toluene. This solution was added dropwise toa solution of potassium ethylate prepared by adding 0.2 g. of potassiumto 25 ml. of ethanol. The reaction mixture was maintained in the range0°-5° C. at which temperature it was stirred for about 1.5 hours afterthe addition had been completed. The reaction mixture was kept in therefrigerator for 48 hours after which time it was diluted with ethylacetate and the separated ethyl acetate layer washed with water. Theethyl acetate layer was dried and the ethyl acetate removed byevaporation in vacuo. TLC showed one major spot. The residue wasdissolved in methanol, and the hydrochloride salt was prepared bypassing gaseous hydrogen chloride into a methanolic solution of thebase. Recrystallization of the hydrochloride salt from a methanol/ethersolvent mixture yielded 290 mg. of methyldl-3-benzyloxy-7-amino-8-oxo-5,6,7,8-tetrahydro-2-naphthoatehydrochloride melting at 195°-200° C.

Analysis Calculated: C, 63.07; H, 5.57; N, 3.87; Cl, 9.80. Found: C,62.95; H, 5.49; N, 4.10; Cl, 10.06.

A suspension of 2 g. of sodium borohydride was prepared in 100 ml. ofethanol. Two and two tenths grams of methyldl-3-benzyloxy-7-amino-8-oxo-5,6,7,8-tetrahydro-2-naphthoatehydrochloride were added thereto in portions. The reaction mixture wasstirred for two hours and was then diluted with water and the aqueousmixture extracted several times with equal volumes of chloroform. Thechloroform extracts were combined and the combined extracts washed withsaturated aqueous sodium chloride and then dried. Evaporation of thechloroform yielded a residue comprising methyldl-3-benzyloxy-7-amino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoatehydrochloride formed in the above reaction. One and forty-one hundredthsgrams of the hydrochloride salt melting at 160°-5° C. were obtained.Recrystallization from ethanol yielded crystals melting at 172°-5° C.

Analysis Calculated: C, 62.72; H, 6.09; N, 3.85; Cl, 9.74. Found: C,62.90; H, 6.33; N, 3.77; Cl, 9.54.

Two and eighteen hundredths grams of methyldl-3-benzyloxy-7-amino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoatehydrochloride, 500 mg. of sodium acetate, 380 mg. of sodiumcyanoborohydride, 4 ml. of propionaldehyde and 150 ml. of methanol wereplaced in a reaction vessel which was stirred under a nitrogenatmosphere for about 19 hours. The reaction mixture was then dilutedwith 1N aqueous hydrochloric acid. The aqueous acidic layer was washedwith ether, the ether wash being discarded, and was then made basic with14N ammonium hydroxide. The resulting alkaline aqueous layer wasextracted several times with equal volumes of chloroform. The chloroformextracts were combined and the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the chloroformyielded a residue which, by TLC, showed one major spot. The residue wasdissolved in chloroform and the chloroform solution chromatographed over35 g. of florisil using chloroform containing small quantities ofmethanol as the eluant. Fractions shown by TLC to contain methyldl-3-benzyloxy-7-di-n-propylamino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoatewere combined and the solvent evaporated therefrom. The resultingresidue was dissolved in ethanol and gaseous hydrogen chloride passedinto the ethanolic solution thus forming the hydrochloride salt.Recrystallization of the solid hydrochloride salt yielded 1.55 g. ofmethyl dl-3-benzyloxy-7-di-n-propylamino-8-hydroxy-2-naphthoatehydrochloride melting at 199°-200° C.

Analysis Calculated: C, 67.03; H, 7.65; N, 3.13; Cl, 7.91. Found: C,66.98; H, 7.76; N, 3.02; Cl, 7.61.

One and five tenths grams of methyldl-3-benzyloxy-7-di-n-propylamino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoatehydrochloride were dissolved in 5 ml. of water and 50 ml. of methanol.One gram of palladium-on-carbon was added and the resulting mixture washydrogenated at 60 psi at a temperature of about 50° C. After thehydrogenation was complete, the hydrogenation mixture was filtered toremove the catalyst and the solvent evaporated from the filtrate. Thethus-obtained residue was suspended in dilute aqueous sodium bicarbonateand the bicarbonate suspension extracted several times with equalvolumes of chloroform. The chloroform extracts were combined and thecombined extracts washed with saturated aqueous sodium chloride and thendried. Evaporation of the solvent yielded methyldl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthoate. Thehydrochloride salt was prepared in ethanol solution, during which time atrans-esterification reaction apparently occurred since the productisolated was ethyldl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthoatehydrochloride. Four hundred and ten mg. of the hydrochloride saltmelting at 202°-4° C. were obtained after recrystallization from anethanol/ether solvent mixture.

Mass spectrum: molecular ion at 319.

Analysis Calculated: C, 64.12; H, 8.50; N, 3.94; Cl, 9.96. Found: C,63.47; H, 8.10; N, 4.35; Cl, 10.15.

Three hundred sixty mg. of ethyldl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthoatehydrochloride were dissolved in 100 ml. of methanol and the methanolicsolution cooled to about 0° C. The cooled solution was then saturatedwith gaseous ammonia. The amidation mixture was left at ambienttemperature under essentially anhydrous conditions for about 5 days. Thecourse of the reaction was followed during this time by TLC which showedincreasing amounts of a more polar material, presumably the carboxamide,and lesser amounts of starting material. Evaporation of the reactionmixture in vacuo yielded a solid material which melted at 272°-4° C.with decomposition after recrystallization from ethanol; yield=280 mg.ofdl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamide.

Analysis Calculated: C, 62.47; H, 8.33; N, 8.57; Cl, 10.85. Found: C,62.26; H, 8.26; N, 8.50; Cl, 10.69.

The alkylation of3-benzyloxy-7-amino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoate methylester hydrochloride was repeated replacing propionaldehyde withformaldehyde. Methyldl-3-benzyloxy-7-dimethylamino-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoatehydrochloride thus prepared melted at 192°-3° C. after recrystallizationfrom ethanol.

Analysis Calculated: C, 64.36; H, 6.69; N, 3.57; Cl, 9.05. Found: C,64.61; H, 6.76; N, 3.68; Cl, 8.81.

The compound was converted todl-3-hydroxy-7-dimethylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideby the above procedures.

Following the above procedure, but starting with 59 g. of methyl2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-naphthoate, 43 g. of methyl2-benzyloxy-5-oximino-5,6,7,8-tetrahydro-1-naphthoate were obtainedmelting at 178°-180° C.

Methyl2-benzyloxy-5-benzenesulfonyloximino-5,6,7,8-tetrahydro-1-naphthoate wasnext prepared and melted at 135°-7° C.; yield=46.5 g. from 40 g. ofoximino compound.

Fifty grams of methyl2-benzyloxy-5-benzenesulfonyloximino-5,6,7,8-tetrahydro-1-naphthoatewere treated with potassium ethylate in toluene solution to yield about22 g. of methyldl-2-benzyloxy-5-oxo-6-amino-5,6,7,8-tetrahydro-1-naphthoatehydrochloride melting at about 220° C. with decomposition afterrecrystallization from ethanol.

Twenty-two and four tenths grams of methyldl-2-benzyloxy-5-oxo-6-amino-5,6,7,8-tetrahydro-1-naphthoatehydrochloride were reduced with sodium borohydride in ethanol to producethe corresponding 5-hydroxy compound isolated as a hydrochloride salt.This compound was alkylated with propionaldehyde in the presence ofsodium cyanoborohydride in methanol solution to yield methyldl-2-benzyloxy-5-hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthoateas the hydrochloride salt. (8.3 g.) melting at about 215°-6° C.

Analysis Calculated: C, 67.03; H, 7.65; N, 3.13; Cl, 7.91. Found: C,66.75; H, 7.44; N, 3.25; Cl, 7.71.

Hydrogenation of this compound with palladium-on-carbon in methanol atabout 60 psi and 50° C. gave methyldl-2-hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthoatehydrochloride (2.1 g. of starting material yielded 710 mg. ofhydrochloride salt) M.P.=195°-6° C. after recrystallization from anether/ethanol solvent mixture.

Analysis Calculated: C, 63.24; H, 8.26; N, 4.10; Cl, 10.37. Found: C,63.04; H, 8.27; N, 4.33; Cl, 10.56.

This ester is readily converted to the corresponding carboxamide by theprocedure of Example 1.

EXAMPLE 4 Alternate preparation ofdl-2-Hydroxy-6-amino-5,6,7,8-tetrahydronaphthalene-1-carboxamide

One-half gram of methyldl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (from Example 1)were dissolved in 20 ml. of ethanol to which were added 20 ml. of 50%(w/v) aqueous sodium hydroxide. This mixture was heated at about 100° C.for 18 hours, after which time the reaction mixture was poured into anice-water mixture. Sufficient 12N aqueous hydrochloric acid was added tomake the reaction mixture acidic.dl-2-Benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoic acid formed in theabove reaction, being insoluble in the acidic layer, separated and wasdissolved with several 3:1 chloroform/isopropanol extracts. The organicextracts were combined and the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the solvent invacuo yielded a dark viscous oil which was dissolved in chloroform andthe chloroform solution chromatographed over silica gel using chloroformcontaining increasing quantities (0-5%) of methanol as the eluant.Fractions shown by TLC to contain the desired naphthoic acid werecombined and the solvent removed therefrom. The residual golden yellowoil thus obtained was dissolved in ether and hexane added to theethereal solution to the point of incipient precipitation. A yellowcrystalline material, M.P.=74°-75° C., comprisingdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoic acid, wasobtained.

Analysis Calculated: C, 66.86; H, 5.30; N, 13.00. Found: C, 66.63; H,5.39; N, 12.79.

Mass spectrum: molecular ion at 323.

Six and fifty-six hundredths grams of the above acid were heated toreflux temperature overnight in 100 ml. of thionyl chloride. Thereaction mixture was then cooled to room temperature and the volatileconstituents removed in vacuo. The residue containingdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoyl chloride wasdiluted with chloroform. About 100 ml. of 14N aqueous ammonium hydroxidewere then added. This new reaction mixture was stirred for one hour atambient temperature and was then diluted with water. The organic phasewas separated and the aqueous phase extracted several times with equalvolumes of chloroform. The chloroform phases were combined and thecombined phases washed with water and with saturated aqueous sodiumchloride and were then dried. Evaporation of the chloroform yielded adark viscous oil. Trituration of the oil with CHCl₃ yielded a solidwhich was filtered and the filter cake dissolved in chloroform. Thechloroform solution was chromatographed over 100 g. of florisil usingchloroform containing increasing amounts (0-2%) of methanol as theeluant. One and eight tenths grams of a solid material were obtainedshowing a single spot (R_(f) =0.46) on TLC in ether;dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide thusprepared melted at 128°-130° C.

Analysis Calculated: C, 67.07; H, 5.63; N, 17.38. Found: C, 66.87; H,5.52; N, 17.48.

Yield was 38.6%.

A solution was prepared by dissolving 0.7 g. ofdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide in 50ml. of ethanol. The solution was placed in a low pressure hydrogenationapparatus and hydrogenated over a palladium-on-carbon catalyst at about60 psi. After the theoretical quantity of hydrogen had been absorbed,the hydrogenation mixture was removed from the apparatus and thecatalyst separated by filtration. Evaporation of the solvent from thefiltrate yieldeddl-2-hydroxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide. Theresidue was dissolved in methanol and gaseous hydrogen chloride passedinto the methanol solution, thus forming the hydrochloride salt. Etherwas added to the solution to the point of incipient precipitation andthe solution was cooled. Crystallinedl-2-hydroxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidehydrochloride thus obtained melted at 245° C.; yield=0.3 g.

Analysis Calculated: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.57; H,6.05; N, 11.36.

Mass spectrum: molecular ion at 296.

EXAMPLE 5 Alternate preparation ofdl-2-Hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide

A solution was prepared from 3.4 g. ofdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (fromExample 4) and 100 ml. of isopropanol. The solution was cooled and 0.5g. sodium borohydride added thereto in small portions. After theaddition had been completed, the reaction mixture was heated to refluxtemperature under a nitrogen blanket for about 18 hours. The reactionmixture was then cooled and the cooled mixture diluted with water. Theaqueous mixture was made acidic by the addition of 1N aqueoushydrochloric acid. The aqueous acidic layer was extracted with ether andthe ether extract discarded. The aqueous acidic layer was made basic bythe addition of 10% aqueous sodium hydroxide. The alkaline layer wasextracted several times with equal volumes of a 3:1 chloroform/methanolsolvent mixture. The organic extracts were combined and the combinedextracts washed with saturated aqueous sodium chloride and then dried.Evaporation of the solvent therefrom yielded a residue comprisingdl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide. TLCindicated a single spot at the origin. An infrared spectrum of the solidindicated no absorption attributable to an azide group. The residue wasdissolved in chloroform and the chloroform solution saturated withgaseous hydrogen chloride. The solvent was removed in vacuo and theresidue dissolved in methanol. Ether was added to the point of incipientprecipitation and the solution was cooled overnight. Forty-eighthundredths grams of tan crystals melting above 235° C. consisting ofdl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidehydrochloride were recovered.

Analysis Calculated: C, 64.96; H, 6.36; N, 8.42. Found: C, 64.72; N,6.54; N, 8.36.

Mass spectrum: molecular ion at 296.

Alternatively, 0.5 g ofdl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide weredissolved in 100 ml. of a 1:1 THF/ethanol solvent mixture. About 1 g. ofRaney nickel were added and the mixture stirred at about 0° C. while 5ml. of hydrazine hydrate were added thereto in dropwise fashion. Afterthe addition had been completed, the reaction mixture was stirred for 4hours at ambient temperature after which time it was filtered. Thesolvent was removed from the filtrate leaving a yellow residue. TLCindicated a single spot with R_(f) =0.63 using a 63:7:27:3chloroform/methanol/acetone/ammonium hydroxide solvent system. Yield ofdl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide was0.46 g. (100%). This 0.46 g. sample was alkylated with propionaldehydeand sodium cyanoborohydride by the procedure of Example 1 to yielddl-2-benzyloxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidehydrochloride. TLC (9:1 chloroform/methanol) R_(f) =0.40.

Mass spectrum: molecular ion at 380.

Analysis Calculated: C, 69.13; H, 7.98; N, 6.72. Found: C, 69.00; H,8.17; N, 6.50.

The benzyl group was removed by hydrogenation over a palladium-on-carboncatalyst according to the procedure of Example 1 to yield about 0.4 g.ofdl-2-hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidehydrochloride.

The hydrochloride salt was converted back to the free base by standardprocedures and the free base chromatographed. Fractions containingdl-2-hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidewere combined and the solvent removed by evaporation. The solid wasreconverted to the hydrochloride salt in ethanol with gaseous hydrogenchloride. Ether was added to the ethanol solution to the point ofincipient precipitation and the solution cooled to about -15° C.Crystallinedl-2-hydroxy-6-di-n-propylamino-5,6,7,8-tetrahydro-1-naphthalenecarboxamidehydrochloride thus purified melted at 168°-170° C.; yield=29.4 mg.

Mass spectrum: molecular ion at 290.

Analysis Calculated: C, 62.47; H, 8.33; N, 8.57; Cl, 10.85. Found: C,62.27; H, 8.04; N, 8.58; Cl, 11.06.

EXAMPLE 6 Alternate preparation of Methyldl-2-Benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthoate

A solution was prepared from about 10 g. of methyl2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-napthoate in 250 ml. of methanolto which was added 10 g. of sodium borohydride in small portions withcooling. After the borohydride had been added, the mixture was stirredfor about 3 hours and then diluted with water. The aqueous layer wasextracted several times with equal volumes of chloroform. The chloroformextracts were combined and the combined extracts were washed withsaturated aqueous sodium chloride and then dried. Evaporation of thesolvent yielded 7.0 g. of an oil comprising methyldl-2-benzyloxy-5-hydroxy-5,6,7,8-tetrahydro-1-naphthoate.

The oily residue was dissolved in 400 ml. of toluene to which were added3 g. of Amberlite®15 as a dehydrating agent. The mixture was distilledunder a nitrogen blanket for about 15 minutes after which time it wasfiltered, and the filtrate cooled. The solvent was removed from thecooled filtrate by evaporation. The resulting residue was recrystallizedfrom an ether/hexane solvent mixture to yield 6.5 g. of methyl2-benzyloxy-7,8-dihydro-1-napthoate melting at 97°-100° C.

The above compound was also prepared by the following sequence ofreactions: Methyl 2-benzyloxy-5-oxo-5,6,7,8-tetrahydro-1-naphthoate wasbrominated with pyridinium bromide perbromide in glacial acetic acid.Methyl dl-2-benzyloxy-5-oxo-6-bromo-5,6,7,8-tetrahydro-1-napthoatemelting at 120°-4° C. was obtained. Twenty-six grams of the bromo ketonewere suspended in 600 ml. of methanol and 20 g. of sodium borohydrideadded. Twenty-four and five tenths grams of methyldl-2-benzyloxy-5-hydroxy-6-bromo-5,6,7,8-tetrahydro-1-naphthoate meltingat 120°-2° C. were obtained. Thirty-one and three tenths grams of thehydroxybromo compound were mixed with 70 g. of zinc dust and 400 ml. ofglacial acetic acid. The reaction mixture was heated at refluxtemperature for about 3 hours under a nitrogen blanket and was thenfiltered. The filtrate was poured over ice and the aqueous mixtureextracted with ethyl acetate. The ethyl acetate layer was separated andthe separated layer washed with water, aqueous sodium bicarbonate, againwith water, and finally with saturated aqueous sodium chloride. Theorganic layer was dried and the solvent was evaporated therefrom invacuo. Seventeen and five tenths grams of methyl2-benzyloxy-7,8-dihydro-1-naphthoate melting at 88°-92° C. were obtainedby this route.

A reaction mixture was prepared from 6.5 g. of methyl2-benzyloxy-7,8-dihydro-1-naphthoate, 4.8 g. of 85% m-chloroperbenzoicacid, 250 ml. of chloroform and 25 ml. of anhydrous ethanol. Thereaction mixture was allowed to remain overnight at ambient temperature.Evaporation of the volatile constituents in vacuo left a residue whichwas dissolved in chloroform. The chloroform solution was filteredthrough about 150 g. of alumina (grade I). Two and three tenths grams ofmethyl dl-2-benzyloxy-5-ethoxy-6-hydroxy-5,6,7,8-tetrahydro-1-naphthoatemelting at 133°-7° C. were obtained from the filtrate aftercrystallization from an ether-hexane solvent mixture.

Analysis calculated: C, 70.77; H, 6.79. Found: C, 70.72; H, 6.66.

Nine and six tenth grams of methyldl-2-benzyloxy-5-ethoxy-6-hydroxy-5,6,7,8-tetrahydro-1-naphthoate weremixed with 4 g. of Amberlite®15 and 250 ml. of toluene. The mixture washeated to refluxing temperature for about 15 minutes and was thenfiltered and the filtrate cooled. Evaporation of the filtrate to drynessyielded a residue which was dissolved in 300 ml. of methanol to whichwas added 23 g. of ammonium acetate. Ten grams of sodiumcyanoborohydride were added thereto in portions. The reaction mixturewas stirred at ambient temperature under a nitrogen blanket overnight.It was then diluted with 1N aqueous hydrochloric acid and the acidiclayer extracted with ether. The ether extract was discarded. The aqueouslayer was made basic with 14N ammonium hydroxide and the alkaline layerextracted several times with equal volumes of chloroform. The chloroformextracts were combined and the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the chloroform invacuo yielded a residue comprising methyldl-2-benzyloxy-6-amino-5,6,7,8-tetrahydro-1-naphthoate. The free basewas dissolved in ethanol and converted to the hydrochloride salt by theaddition of 2 ml. of 12N aqueous hydrochloric acid. One and twenty-fivehundredths grams of hydrochloride salt were obtained. The hydrochloridesalt was converted to the free base by standard procedures. Sixty-fourhundredths grams of free base thus obtained were dissolved in boilingmethanol to which was added 280 mg. of oxalic acid dihydrate. Sixhundred milligrams of the oxalate salt of methyldl-2-benzyoxy-6-amino-5,6,7,8-tetrahydro-1-naphthoate melting at 181°-3°C. were obtained.

Analysis calculated: C, 62.84; H, 5.78; N, 3.49. Found: C, 62.64; H,5.79; N, 3.44.

The primary amine thus prepared can be debenzylated by hydrogenationover a palladium-on-carbon catalyst and the resulting compound convertedto the carboxamide by procedures set forth in the above examples.Alternatively, the amine can be alkylated with formaldehyde,acetaldehyde or propionaldehyde in the presence of sodiumcyanoborohydride and the resulting dialkylamine debenzylated and thefree-hydroxy compound converted to the carboxamide also by procedures ofthe above examples.

EXAMPLE 7 Preparation ofdl-3-Hydroxy-7-amino-5,6,7,8-tetrahydro-2-naphthlenecarboxamide

Twenty-four and eight tenths grams of methyl3-benzyloxy-8-oxo-5,6,7,8-tetrahydro-2-naphthoate were dissolved in amixture of 200 ml. of THF and 200 ml. of methanol. Twenty-eight grams ofpyridinium perbromide hydrobromide were added and the reaction mixturestirred at ambient temperature for 2.5 hours after which time it wasdiluted with water and the resulting aqueous mixture extracted withchloroform. The chloroform extract containing methyldl-3-benzyloxy-7-bromo-8-oxo-5,6,7,8-tetrahydro-2-naphthoate was washedwith saturated aqueous sodium chloride and then dried. The solvent wasremoved therefrom by evaporation. The resulting residue was dissolved in500 ml. of DMF containing 10 ml. of glacial acetic acid. The solutionwas cooled in an ice-water bath to about 0° C. A solution of 12 g. ofsodium azide in 100 ml. of water was added. The reaction mixture wascooled for 2 hours, and was then diluted with water. The aqueous mixtureextracted with ethyl acetate. The ethyl acetate extract was washed withwater and with saturated aqueous sodium chloride and was then dried.Evaporation of the ethyl acetate yielded a residue comprising methyldl-3-benzyloxy-7-azido-8-oxo-5,6,7,8-tetrahydro-2-naphthoate. Theresidue was dissolved in THF and the THF solution diluted with 400 ml.of methanol. The solution was cooled to about 0° C. and 20 g. of sodiumborohydride added thereto in portions. The reaction mixture was stirredat ambient temperature for about 2 hours and was then diluted withwater, and the resulting aqueous mixture extracted with chloroform. Thechloroform layer was separated; the separated layer washed with waterand with saturated aqueous sodium chloride and then dried. Evaporationof the chloroform yielded methyldl-3-benzyloxy-7-azido-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoate. Thisresidue was chromatographed over 400 g. of florisil using hexanecontaining increasing amounts (0-100%) ether as the eluant. Twenty gramsof the hydroxy azide were obtained from fractions shown by TLC tocontain the desired material.

About 20 g. of methyldl-3-benzyloxy-7-azido-8-hydroxy-5,6,7,8-tetrahydro-2-naphthoate thusobtained were dissolved in 150 ml. of carbon tetrachloride to which wasadded 25 g. of triethylsilane and 30 ml. of trifluoroacetic acid. Thereaction mixture was stirred for about 20 minutes at room temperatureand was then poured over ice. The aqueous mixture was made basic with14N ammonium hydroxide. The alkaline layer was extracted withchloroform. The chloroform extract was separated and the separatedextract washed with saturated aqueous sodium chloride and then dried.Evaporation of the chloroform yielded methyldl-3-benzyloxy-7-azido-5,6,7,8-tetrahydro-2-naphthoate. The residue wasdissolved in 250 ml. of THF and 250 ml. of methanol. Ten grams of Raneynickel were added to this mixture followed by the dropwise addition of10 ml. of 85% hydrazine hydrate in 40 ml. of methanol. This reactionmixture was stirred for about 30 minutes and then filtered. The filtratewas concentrated in vacuo and the concentrated filtrate diluted withethyl acetate. The ethyl acetate layer was extracted several times with10% aqueous hydrochloric acid. The aqueous layer and acidic extractswere then made basic with 14N ammonium hydroxide and the basic layerextracted with chloroform. The chloroform extract was separated and theseparated extract washed with saturated aqueous sodium chloride and thendried. Evaporation of the solvent yielded 15.5 g. of methyldl-3-benzyloxy-7-amino-5,6,7,8-tetrahydro-2-naphthoate.

A portion of the above free base was converted to the hydrochloridesalt. Eight and nine tenths grams of this salt were dissolved inmethanol containing 1 ml. of water. Two grams of 5% palladium-on-carbonwere added and the mixture hydrogenated at 60 psi. The hydrogenationmixture was then filtered and the filtrate evaporated to dryness invacuo. A white solid shown by TLC to consist of a single spot comprisingmethyl dl-3-hydroxy-7-amino-5,6,7,8-tetrahydro-2-naphthoatehydrochloride was obtained. This white solid was dissolved in methanoland the methanol solution cooled to about 0° C. The cooled solution wassaturated with gaseous ammonia and the resulting mixture allowed toremain at ambient temperature for about 17 days. At this time, TLCindicated the amidation reaction had gone substantially to completion.The reaction mixture was decolorized with carbon and filtered and thefiltrate concentrated in vacuo to yield about 3.5 g. ofdl-3-hydroxy-7-amino-5,6,7,8-tetrahydro-2-naphthalenecarboxamidehydrochloride melting at about 300° C.

Analysis Calculated: C, 54.44; H, 6.23; N, 11.54; Cl, 14.61. Found: C,54.17; H, 6.07; N, 11.30; Cl, 14.45.

As previously stated, the compounds of this invention are dopamineagonists. As such, one of their properties, shared by many dopamineagonists, is the ability to lower blood pressure in anesthetizedspontaneously hypertensive rats (SHR). Table 1 which follows gives theresults of testing compounds of this invention which lowered the bloodpressure of anesthetized SHR at dose levels of 1 mg./kg. or lower. Inthe Table, the first 4 columns give the substitution pattern of thehydroxyaminonaphthalene carboxamide and the second 4 columns the percentblood pressure lowering±standard error for the particular compound at 4different dose levels.

                                      TABLE 1                                     __________________________________________________________________________     ##STR12##                                                                                    Percent lowering of mean arterial blood pressure                              anesthetized spontaneously hypertensive rats                  Substitution Pattern                                                                          Dose                                                          R    R.sup.1                                                                            R.sup.2                                                                          R.sup.3                                                                          7 mcg./kg.                                                                          10 mcg./kg.                                                                          100 mcg./kg.                                                                         1 mg./kg.                                 __________________________________________________________________________    H    CONH.sub.2                                                                         H  H  -3.6 ± 0.4                                                                       -5.2 ± 0.8                                                                        -10.2 ± 1.2                                                                       -18.3 ± 4.3                            H    "    Me Me -6.2 ± 0.7                                                                       -14.0 ± 0.5                                                                       -25.1 ± 3.0                                                                       -32.5 ± 2.2                            H    "    n-Pr                                                                             n-Pr                                                                             -6.8 ± 0.5                                                                       -19.6 ± 0.8                                                                       -35.9 ± 2.3                                                                       -41.9 ± 1.6                            CONH.sub.2                                                                         H    Me Me -6.8 ± 0.3                                                                       -5.7 ± 0.3                                                                         -6.7 ±  0.8                                                                       -6.0 ± 0.5                            __________________________________________________________________________

Compounds with dopaminergic or dopamine agonist activity also affectturning behavior in a test procedure utilizing6-hydroxydopamine-lesioned rats. In this test,nigro-neostriatal-lesioned rats, prepared by the procedure of Ungerstedtand Arbuthnott, Brain Res, 24, 485 (1970), are employed. A compoundhaving dopamine agonist activity, upon injection, causes the rats toturn in circles contralateral to the side of the lesion. After a latencyperiod, which varies from compound to compound, the number of turns iscounted over a 15-minute period. The drugs to be administered aredissolved in water and the resulting aqueous solution injected into therat by the intraperitoneal route at a 1 mg./kg. dose level. Table 2which follows gives the results of such tests. In Table 2, column 1gives the name of the compound, column 2 the percent of rats exhibitingturning behavior and column 3 the average number of turns.

                  TABLE 2                                                         ______________________________________                                        Turning Behavior                                                                                   Percentage of                                                                 rats exhibiting                                                                          Number                                                             turning    of                                            Name of Compound     behavior   turns                                         ______________________________________                                        dl-3-hydroxy-7-dimethylamino-5,6,7,8-                                                              50         20                                            tetrahydronaphthalene-2-carboxamide                                           dl-3-hydroxy-7-di-n-propylamino-5,6,7,8-                                                           75         71                                            tetrahydronaphthalene-2-carboxamide                                           ______________________________________                                    

The compounds of this invention are also useful as inhibitors ofprolactin secretion. Dopaminergic drugs with such activity can beemployed in the treatment of inappropriate lactation, such as postpartumlactation and galactorrhea. The compounds of this invention have beenshown to inhibit prolactin secretion according to the followingprocedure: Adult male rats of the Sprague-Dawley strain weighing about200 g. were housed in an air-conditioned room with controlled lighting(lights on 6 a.m.-8 p.m.) and fed lab chow and water ad libitum. Eachrat received an intraperitoneal injection of 2.0 mg. of reserpine inaqueous suspension 18 hours before administration of the test compound.The purpose of the reserpine was to keep prolactin levels uniformlyelevated. The compounds under test were dissolved in water and wereinjected intraperitoneally at a 1 mg./kg. dose level. Each compound wasadministered to a group of 10 rats, and a control group of 10 intactmales received an equivalent amount of solvent only. One hour aftertreatment all rats were killed by decapitation, and 150 μl. aliquots ofserum were assayed for prolactin.

The results of this prolactin secretion inhibition test are given inTable 3 below. In the table, column 1 gives the name of the compound andcolumn 2, the percent inhibition of prolactin secretion. The dosage was1 mg./kg.

                  TABLE 3                                                         ______________________________________                                        Prolactin Secretion Inhibition                                                                     Percent Inhibition of                                                         Prolactin Secretion                                      Name of Compound     with Confidence Level                                    ______________________________________                                        dl-3-hydroxy-7-di-n-propylamino-5,6,7,8-                                                           88 (p < 0.01)                                            tetrahydronaphthalene-2-carboxamide                                           dl-3-hydroxy-7-dimethylamino-5,6,7,8-                                                              36 (p < 0.05)                                            tetrahydronaphthalene-2-carboxamide                                           dl-2-hydroxy-6-amino-5,6,7,8-tetrahydro-                                                           13 (N.S.)                                                naphthalene-1-carboxamide                                                     dl-3-hydroxy-7-amino-5,6,7,8-tetrahydro-                                                           18 (N.S.)                                                naphthalene-2-carboxamide                                                     dl-2-hydroxy-6-di-n-propylamino-5,6,7,8-                                                           12 (N.S.)                                                tetrahydronaphthalene-1-carboxamide                                           ______________________________________                                    

In using the dopaminergic compounds of this invention to inhibitprolactin secretion or to treat Parkinson's syndrome or as hypotensivedrugs or for other dopaminergic pharmacologic action, a compoundaccording to Formula I, above, or a salt thereof with apharmaceutically-acceptable acid, is administered to a subject sufferingfrom Parkinsonism or hypertension, or needing to have his or herprolactin level reduced, in an amount effective to alleviate some of thesymptoms of Parkinsonism or to reduce blood pressure or to reduce anelevated prolactin level. Oral administration is preferred. Ifparenteral administration is used, administration is preferably by thesubcutaneous route using an appropriate pharmaceutical formulation.Other modes of parenteral administration such as intraperitoneal,intramuscular, or intravenous routes are equally effective. Inparticular, with intravenous or intramuscular administration, a watersoluble pharmaceutically-acceptable salt is employed. For oraladministration, a compound according to Formula I either as the freebase or in the form of a salt thereof, is mixed with standardpharmaceutical excipients and the mixture loaded into empty telescopinggelatin capsules or pressed into tablets. The oral dosage should be inthe range 0.01-10 mg./kg. of mammalian body weight and the parenteraldose in the range 0.0025 to 2.5 mg./kg.

We claim:
 1. A method for reducing elevated blood pressure in a mammalhaving high blood pressure and in need of treatment which comprisesadministering to said mammal a hypotensive dose of a drug of the formula##STR13## wherein one of R and R¹ is H and the other is CONH₂, R² and R³are individually H, methyl, ethyl or n-propyl, and apharmaceutically-acceptable acid addition salt thereof formed with anon-toxic acid.
 2. A process according to claim 1 in whichdl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 3. A process according to claim 1 in whichdl-3-hydroxy-7-dimethylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 4. A method of inhibiting the secretion ofprolactin in mammals which comprises administering to a mammal having acondition accompanied by excess prolactin secretion and in need oftreatment a prolactin secretion inhibiting dose of a drug of the formula##STR14## wherein one of R and R¹ is H and the other is CONH₂, R² and R³are individually H, methyl, ethyl or n-propyl, and apharmaceutically-acceptable acid addition salt thereof formed with anon-toxic acid.
 5. A process according to claim 4 in whichdl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 6. A process according to claim 4 in whichdl-3-hydroxy-7-dimethylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 7. A method of treating Parkinson's Syndromewhich comprises administering to a human suffering from Parkinson'sSyndrome and in need of treatment, a dose of a drug of the formula##STR15## wherein one of R and R¹ is H and the other is CONH₂, R² and R³are individually H, methyl, ethyl or n-propyl, and apharmaceutically-acceptable acid addition salts thereof formed with anon-toxic acid effective to alleviate some or all of the manifestationsof Parkinson's Syndrome.
 8. A process according to claim 7 in whichdl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 9. A process according to claim 7 in whichdl-3-hydroxy-7-dimethylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the drug administered.
 10. A pharmaceutical formulation in unitdosage form adapted for administration to achieve a dopaminergic effectcontaining per unit dosage a dopaminergically-effective amount of a drugof the formula U.S. Ser. No. 588,180 ##STR16## wherein one of R and R¹is H and the other is CONH₂, R² and R³ are individually H, methyl, ethylor n-propyl, and a pharmaceutically-acceptable acid addition saltthereof formed with a non-toxic acid plus one or more pharmaceuticalexcipients.
 11. A formulation according to claim 10 in whichdl-3-hydroxy-7-di-n-propylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the active drug.
 12. A formulation according to claim 10 in whichdl-3-hydroxy-7-dimethylamino-5,6,7,8-tetrahydro-2-naphthalenecarboxamideis the active drug.